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. 2011 Jun;9(6):1133-42.
doi: 10.1111/j.1538-7836.2011.04272.x.

Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism

J A Heit  1 , J M Cunningham, T M Petterson, S M Armasu, D N Rider, M DE Andrade
Affiliations

Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism

J A Heit et al. J Thromb Haemost. 2011 Jun.

Abstract

Background: Venous thromboembolism (VTE) is highly heritable (estimated heritability [h(2)]=0.62) and likely to be a result of multigenic action.

Objective: To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE.

Methods: Non-Hispanic adults of European ancestry with objectively-diagnosed VTE, and age- and sex- matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n=12296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke.

Results: Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non-O blood type, and a novel association with ABO rs2519093 (OR=1.68, P-value=8.08×10(-16) ) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non-carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non-O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non-carriers. The ABO rs2519093 population-attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non-O and ABO rs2519093 was 0.40.

Conclusions: Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non-Hispanic adults of European ancestry.

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Conflict of interest statement

Conflict of Interest Disclosure

The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Manhattan plot of association results between VTE and candidate gene SNPs by chromosome. The x-axis displays the chromosomes and the y-axis displays the −log10 p-values. The horizontal line represents the −log10 of the Bonferroni corrected p-value (−log[4.0E-06] = 5.40). The significant results (Bonferroni corrected p-value < 4.0E-06) are labeled by gene name and SNP rs number. The r2 value between the two F5 SNPs is 0. The r2 values between the ABO SNPs are as depicted in details in Figure 2.
Figure 2
Figure 2
Haploview linkage disequilibrium plot of ABO SNPs (n=17). Blocks represent SNPs in high linkage disequilibrium. Greater color intensity corresponds to a higher level of linkage disequilibrium given by D’. The value inside each cell represents linkage disequilibrium given by r2. Blue rectangles outline the ABO blood group SNPs (homozygous deletion on rs8176719 determines O blood type). Green rectangles outline ABO SNPs significantly associated with VTE. ABO SNPs from HapMap build 36.3 are displayed above the Haploview plot.
See this image and copyright information in PMC

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